The diagnosis and management of

Dementia with Lewy bodies

John O’Brien

Professor of Old Age Psychiatry

University of Cambridge

Includes dementia with Lewy bodies (dementia first) and

dementia in Parkinson’s disease (“one year rule”)

Dementia develops in >80% PD cases 1

Degenerative dementia, a synucleinopathy with

characteristic clinical and pathological features (Lewy bodies

and neurites; plaques (mainly non-neuritic), few tangles)

Common, currently 4 - 7.5% of all dementias diagnosed

(pathological series up to 15-20%) 2

Age-related. Classically males > females 2

Lewy body dementias

1Aarsland et al, 2008; 2Vann-Jones and O’Brien 2014

Core clinical features

Core clinical features

Preserved memory, attentional

and visuospatial impairment

AD DLB

Recall: 0/5 3/5

Core clinical features

Preserved memory, attentional

and visuospatial impairment

Parkinsonism

AD DLB

Recall: 0/5 3/5

Core clinical features

Preserved memory, attentional

and visuospatial impairment

Parkinsonism

AD DLB

Recall: 0/5 3/5

Recurrent visual

hallucinations

Core clinical features

Preserved memory, attentional

and visuospatial impairment

Parkinsonism

Fluctuation

AD DLB

Recall: 0/5 3/5

minute to minute

/ hour by hour

variation

Recurrent visual

hallucinations

Core clinical features

Preserved memory, attentional

and visuospatial impairment

Parkinsonism

Fluctuation REM sleep behaviour

Disorder (RBD)

AD DLB

Recall: 0/5 3/5

minute to minute

/ hour by hour

variation

Recurrent visual

hallucinations

REM-sleep behaviour disorder

• Occurs in 50-80% DLB subjects; can occur years before diagnosis (also before PD)

• Characterised by:

• loss of the normal atonia during REM sleep and associated “dream enactment”

• vocalisations

• Potential violent motor behaviours; dream content is often of a chasing, violent or attacking theme

• For formal diagnosis, a full sleep history (often with collateral history from bed partner) and polysomnography are required

Boeve et al, Sleep Disorders 2011

REM-sleep behaviour disorder

Have you ever seen the patient appear to “act

out his/her dreams” while sleeping? (punched or

flailed arms in the air, shouted or screamed)?

Single question from 16 item Mayo Sleep questionnaire had sensitivity of

98% and spec of 74% for diagnosis of RBD (proven using

polysomnography) in an ageing and dementia cohort (n=176)

Boeve et al, J Clin Sleep Med, 2013

Single question had sens of 100% and spec of 95% for diagnosis of RBD

(proven using polysomnography) in a community cohort (n=128)

Brain imaging changes in DLB

Relative structural preservation

White matter changes on DTI

Parieto-occipital hypometabolism

Dopaminergic loss in striatum

50% cases amyloid positive

Barber et al 1999; Rodriguez et al, 2012; Watson et al, 2012; O’Brien et al, 2004; Villemagne et al, 2011; Mak et al, 2015; Donaghy et al, 2018

Barber et al 1999; Rodriguez et al, 2012; Watson et al, 2012; O’Brien et al, 2004; Villemagne et al, 2011; Mak et al, 2015; Donaghy et al, 2018

Brain imaging changes in DLB

Relative structural preservation

White matter changes on DTI

Parieto-occipital hypometabolism

Dopaminergic loss in striatum

50% cases amyloid positive

Brain imaging changes in DLB

Relative structural preservation

White matter changes on DTI

Parieto-occipital hypometabolism

Dopaminergic loss in striatum

50% cases amyloid positive

Barber et al 1999; Rodriguez et al, 2012; Watson et al, 2012; O’Brien et al, 2004; Villemagne et al, 2011; Mak et al, 2015; Donaghy et al, 2018

Brain imaging changes in DLB

Relative structural preservation

White matter changes on DTI

Parieto-occipital hypometabolism

Dopaminergic loss in striatum

50% cases amyloid positive

Barber et al 1999; Rodriguez et al, 2012; Watson et al, 2012; O’Brien et al, 2004; Villemagne et al, 2011; Mak et al, 2015; Donaghy et al, 2018

Brain imaging changes in DLB

Relative structural preservation

White matter changes on DTI

Parieto-occipital hypometabolism

Dopaminergic loss in striatum

50% cases amyloid positive

Barber et al 1999; Rodriguez et al, 2012; Watson et al, 2012; O’Brien et al, 2004; Villemagne et al, 2011; Mak et al, 2015; Donaghy et al, 2018

AD

Zhong et al, 2014

Subcortical pattern of atrophy in DLB

Pattern of temporal lobe/ insula and basal ganglia atrophy in DLB c/w controls

218 DLB v 219 Controls

Guerreiro et al, 2017

Genetics of DLB

• First GWAS study in DLB: 1742 DLB cases, 4452

controls

• Significant, replicated, effects for 3 genes:

• ApoE 4 (OR 2.4)

• SNCA (synuclein gene) (OR 0.73)

• GBA (glucocerebrosidase gene) (OR 2.55)

• Results supported some similarities to AD and PD,

but unique genetic profile separate to either

Impact of DLB

Lowest QoL in LBD

IDEAL study

Wu et al, 2018

Higher acute hospital resource use in LBD

Most common reasons, infections, falls/fractures

and circulatory collapse

Mueller et al, 2018

Diagnosis

DSM-5, APA 2013, very similar to third consensus report, McKeith et al, Neurology, 2005

DSM-5: Neurocognitive disorder

with Lewy bodies (Major or Mild)

• Core diagnostic features

• Fluctuating cognition

• Recurrent visual hallucinations

• Spontaneous parkinsonism after cognitive decline

• Suggestive diagnostic features

• RBD

• Severe neuroleptic sensitivity

New criteria for Dementia with Lewy bodies

Evidence of cognitive impairment (esp characteristic profile) of sufficient magnitude to interfere with normal social and occupational function

Core features (need two or one + biomarker for Probable DLB)

Fluctuating cognitive impairment – 80%

Recurrent complex visual hallucinations – 70%

Spontaneous features of parkinsonism – 25-50% (75% eventually)

RBD

Indicative biomarkers

Low dopamine transporter uptake in basal ganglia demonstrated by

SPECT or PET imaging

Abnormal cardiac MIBG imaging

RBD confirmed by polysomnography

McKeith et al, Neurology, 2017

Indicative biomarkers

Low dopamine transporter uptake

in basal ganglia

Abnormal cardiac MIBG imaging

Polysomnography confirmed

RBD

New criteria for Dementia with Lewy bodies

McKeith et al, Neurology, 2017

Supportive clinical features Neuroleptic (antipsychotic) sensitivity

Postural instability

Repeated falls

Syncope or transient episodes of unresponsiveness

Severe autonomic dysfunction

Hypersomnia

Hyposmia

Hallucinations in other modalities

Systematized delusions

Apathy

Anxiety

Depression

New criteria for Dementia with Lewy bodies

McKeith et al, Neurology, 2017

Supportive biomarkers

Preservation of medial temporal lobe

on structural imaging

Abnormal perfusion SPECT/ metabolic (FDG)

PET with occipital changes and/or

“cingulate island sign”

Prominent posterior slow wave activity on EEG with periodic fluctuations

New criteria for Dementia with Lewy bodies

McKeith et al, Neurology, 2017

DLB AD

DIAMOND-Lewy Programme

Improving the DIAgnosis and Management Of Neurodegenerative Dementia of Lewy body type

NIHR Programme. UK study which aims to bring together brief diagnostic toolkit with a cluster randomised study of a management pathway

DIAMOND-Lewy Programme

North East

East Anglia

2. What are the

barriers to diagnosing

LBD more often?

1. How often is Lewy

body dementia

currently diagnosed

and how is it

managed?

3. What are the best

evidenced based

ways to manage

LBD?

4. What are the

best ways to

diagnose LBD?

5. Trial: Does the introduction of a

comprehensive diagnostic and

management pathway improve outcomes

for patients and carers?

• 9499 consecutive cases

seen

• 4.6% of dementia

subjects diagnosed with

DLB across both regions

• DLB prevalence was

significantly higher in the

North East (p<0.01)

• DLB cases in East Anglia

had significantly more

core features (P=0.007)

Kane et al, 2018

Regional differences in diagnostic rates

0

2

4

6

8

10

DLB

Pre

vale

nce

(%

)

Thomas et al, IJGP, 2016; Thomas et al IJGP 2018

Just type DIAMOND Lewy into your

favourite search engine

Outcome

Outcome in DLB

C-PBB3

• Relatively few studies

• Not always consistent

• Most evidence suggests similar rates of

cognitive decline to AD1,2

• Maybe greater functional decline in DLB3

• Mortality in DLB may be increased3. In a

previous imaging study 9/35 DLB died in one

year c/w 0/36 AD (26% v 0%; p=0.009) 4,5

1Walker et al, 2012; 2Aasland et al, 2012; 3Williams et al, 2006; 4Watson et al, 2012; 5Mak et al, 2015

Survival analysis (till 2015) of DLB and

comparison AD cases

Survival analysis

accounting for age,

antipsychotic prescribing

and frailty

AD survival:

6.7 years for males and

7.0 years for females

DLB survival:

3.3 years for males and

4.0 years for females

DLB

AD

Price et al, BMJ Open, 2017

Management

The challenges of DLB management

• Multiple symptoms:

• Cognitive impairments

• Neuropsychiatric features

• Motor problems

• Autonomic symptoms

• Treatments for one symptom (e.g. motor) may make other

symptoms worse (e.g. visual hallucinations)

• Fluctuations makes treatment response difficult to assess

• Carers, patients and clinicians may all have a different

view on what the main problems are

• Limited evidence base

Meta-analysis of CholEI in Lewy body dementia

Stinton et al, 2015

MMSE

Meta-analysis of CholEI in Lewy body dementia

Stinton et al, 2015

Global

Outcome

N = 120 DLB

30% improvement (Neuropsychiatric

inventory) from baseline at wk 20

67% rivastigmine group

30% placebo group

p<=0.03

MMSE treatment vs. control 1.5 points vs.

-0.1 points (p=0.07)

McKeith et al, Neurology, 2001

Donepezil in DLB – a RCT of 140 subjects

Mori et al, Ann Neurol, 2013

MMSE sig

improved

(2-3 points)

• Improvement in cognition and global outcome

• No improvement in neuropsychiatric symptoms

• Better response in PDD than DLB

• Improvement in global outcome and neuropsychiatric symptoms in DLB, not PDD or combined group

• No cognitive improvement

Aarsland et al, 2009; Emre et al, 2010

Motor symptoms in DLB

• Parkinsonism present in 75%

− Predominantly postural instability/gait difficulty

− Severity similar to age-matched PD

• Major correlate of functional impairment

• Probably undertreated; limited trials but l-dopa improves motor

symptoms in around 35% (c/w PD 65%)

• Mostly well tolerated (>80%), can worsen psychosis, but to a much

lesser extent that dopamine agonists and other agents

Molloy et al, JNNP 2005

Best Practice Guide for the Treatment of

REM Sleep Behaviour Disorder (RBD)

• *Clonazepam 0.25mg

• *Melatonin 3mg

• Quetiapine 12.5mg

*Recommended by DLB consortia report

At bedtime dose

titrated up - all

level B

Aurora et al, 2010

Sleepiness in DLB

• Open label study 20 DLB treated for 12 weeks with armodafinil 125-

250mg. 85% completed study

• Found sig decreased sleepiness, increased wakefulness, improved

global impression and increased carer QoL at 12 weeks

• Some improvements on NPI at 4

• No cognitive or ADL changes

Lapid et al 2017

Mean 6 point improvement

on both scales

DLB and antipsychotics

• Obvious dangers, general increase in mortality and stroke

risk in dementia

• Neuroleptic sensitivity in DLB, occurs with atypicals as well

as typicals (but probably less frequently)

• Tolerance of antipsychotics does not exclude DLB

• Very little evidence in DLB on which to base clinical practice

• Use very cautiously, initially low dose with expert initiation

and supervision, only when all other options have failed

Evidence base

• Clozapine – good evidence base for PD psychosis, some of the studies

included some PDD subjects

• Risperidone – some positive case reports but side effects problematic,

only RCT showed worsening of psychotic symptoms and 68% dropout

rate (Culo et al, 2010)

• Quetiapine – expert opinion and open studies suggest can be tolerated

and may benefit, the only RCT in DLB was negative, and recent

systematic review shows no evidence of benefit (Desmarais et al, 2016)

• Aripiprazole – some case reports suggest benefit, but also adverse

effects

• Others may have promise (Pimavanserin) but currently evidence in DLB

lacking

Stinton et al, 2015

Connors et al, Psych Med 2017

Search of literature found 21 studies.

Only one large RCT, which found beneficial effects of honey thickened liquids

in reducing aspiration

Other studies of many different interventions, e.g. exercise, environmental

modification, Occupational therapy, simulated presence, music therapy, ECT,

TMS, direct current stimulation, deep brain stimulation

Most were single case reports, most reported benefit of intervention used but

wider interpretation unclear – need for more systematic study of cases series

and, especially, RCTs

Symptom summary

49

LBD

Management

Toolkit

Overview Reference

guidelines

DIAMOND-Lewy Management toolkit

Available mid 2019

Prodromal DLB

• An emerging concept, clear diagnostic criteria do not exist

• Different strategies: identify MCI with LB symptom/biomarker, or take LB

symptom/ biomarker (e.g. RBD) and wait for cognitive decline

• Heterogeneity of presentation a clear challenge

Confusion/

delirium Prodromal

DLB

Motoric

MCI

Psychiatric/

VH,

depression Sleep/RBD Autonomic

Utility of biomarkers in Prodromal DLB

• 33 MCI-LB (probable), 15 MCI-LB (possible), 27 MCI-AD

• Entry on clinical grounds, prob = 2 or more suggestive/ core features;

poss 1 feature only (mean MMSE 26.5)

• Dopaminergic (FP-CIT) SPECT scans rated blind to diagnosis

• Dopaminergic SPECT had:

– Sens 60%, Spec 89% for MCI-LB (probable)

– Sens 40%, Spec 89% for MCI-LB (possible)

• Suggests current biomarkers may be useful in prodromal group

• Other biomarkers (CSF, Skin Bx)

under study

Thomas et al, 2018; Donadio et al, 2017; 2018

Left

Right

Blanc et al, 2015a,b

Cortical thickness changes in prodromal

DLB and prodromal AD

In prodromal DLB, significant

thinning in insular and

anterior cingulate

In prodromal AD, significant

thinning in parietal and

temporal (parahippocampal)

areas and precuneus

Conclusions

• DLB important to diagnose, management is different

• Think DLB when diagnosing or reviewing diagnosis: ask

about RBD, fluctuation/ somnolence and hallucinations;

look for parkinsonism. Consider investigations for indicative

and supportive biomarkers if diagnosis in doubt

• Take holistic approach. CholEI should be prescribed,

consider memantine, treat other symptoms (RBD,

parkinsonism) if required

• Use antipsychotics very cautiously, never typicals

• Prodromal DLB cases can be identified, but more

challenging than Prodromal AD

DIAMOND-Lewy team

Cambridge

• John O’Brien • AJ Surendranathan • Allison Bentley • Louise Lafortune

Warwick

• James Mason

Newcastle • Alan Thomas • Joe Kane • Sally Barker • Nicky Barnett • Louise Allen • Clare Bamford • Tracy Finch • Richard McNally • Luke Vale • Derek Forster • David Burn • John-Paul Taylor • Ian McKeith